Stereospecific process

ABSTRACT

The process depicted, for example, by the formulae ##STR1## R=esterified hydroxy yields valuable intermediates in the manufacture of drugs.

This is a divisional of application Ser. No. 873,456 filed on Jan. 30,1978, now abandoned.

BACKGROUND OF THE INVENTION

U.S. Pat. Nos. 3,312,592; 3,910,930 and 3,914,238 disclosepharmacologically active 2-(2-amino-1-hydroxyethyl)-1,4-benzodioxans,which are obtained as mixtures of diastereoisomers, separable only bycumbersome methods. According to the present invention a stereospecificprocess is provided, yielding intermediates for said compounds in thepure erythro or threo forms, and requiring but simple, inexpensivestarting materials. Moreover, said process is especially suited for theunambiguous preparation of ring-A-substituted 1,4-benzodioxans.

SUMMARY OF THE DISCLOSURE

The present invention concerns and has for its object the provision of anew stereospecific process for the preparation of2(2-substituted-1-hydroxyethyl)-1,4-benzodioxans corresponding toFormula I ##STR2## wherein Ph is unsubstituted 1,2-phenylene or1,2-phenylene substituted by one to three identical or different membersselected from lower alkyl; free, etherified or esterified hydroxy, suchas lower alkoxy, lower alkylenedioxy, benzyloxy, lower alkanoyloxy orhalogeno; trifluoromethyl; or nitro; each of R₁ and R₂ is hydrogen orlower alkyl and R₃ is free or said esterified hydroxy; or a secondary ortertiary amino group, such as mono- or di-lower alkylamino, loweralkyleneimino unsubstituted or substituted in a position separated fromthe nitrogen atom by at least 2 carbon atoms by one member selected fromfree, etherified or esterified hydroxy, such as lower alkoxy, lower orhigher alkanoyloxy, and/or one member selected from lower alkyl,HPh-lower alkyl, HPh, unsubstituted naphthyl or naphthyl substituted asPh, unsubstituted furyl, thiophenyl, pyridyl, benzofuryl,benzothiophenyl, quinolyl, isoquinolyl or ##STR3## or said heterocyclicssubstituted as Ph; or of therapeutically acceptable acid addition saltsthereof; which compounds are either known or new therapeutically usefulproducts, e.g. β-adrenergic blocking or antihypertensive agents, orvaluable intermediates thereof.

Said sterospecific process comprises the following steps: ##STR4##wherein R is CHO or lower alkanoyloxy, M is one equivalent of a metalatom, such as of an alkaline earth or preferably an alkali metal, X is ahalogen atom and one of Y and Z is R₂ and the other is CH₂ X; ##STR5##wherein R₄ is hydrogen, lower alkanoyl, lower haloalkanoyl, HPh--CO,HOOC--C₂ H₄ --CO, or HOOC--Ph--CO and R' is lower alkanoyloxy; ##STR6##wherein one of Y' and Z' is R₂ and the other is CH₂ R₃ ', in which R₃ 'is selected from R₃ but being different from X; ##STR7## wherein R₃ =X;##STR8## wherein R₃ is different from X.

In case Y or Y'=R₂ in III (resulting from the transolefin), theerythro-compounds are obtained, and if Z or Z'=R₂ (resulting from thecis-olefin), the threo-compounds are formed.

The conversion of compounds V into those of Formula I is disclosed insaid U.S. Pat. No. 3,914,238 without reference to a stereochemicallysingle entity.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The 1,2-phenylene group Ph is preferably unsubstituted ormonosubstituted, and its substituents illustrated by the followinggroups; lower alkyl, e.g. methyl, ethyl, n- or i-propyl or -butyl;hydroxy; lower alkoxy, e.g. methoxy, ethoxy, n- or i-propoxy or -butoxy,lower alkylenedioxy, e.g. methylenedioxy, 1,1- or 1,2-ethylenedioxy;benzyloxy; halogeno, e.g. fluoro, chloro or bromo; trifluoromethyl; ornitro.

Each of R₁ and R₂ is preferably hydrogen, but also lower alkyl,advantageously methyl, or another of those mentioned above.

The substituent R₃ is preferably X, especially chloro, but also bromo oriodo; hydroxy or R', e.g. formyloxy, acetoxy, propionyloxy orpivalyloxy. A mono- or di-lower alkylamino group R₃ contains preferablysecondary or tertiary alkyl groups with 3 to 7 carbon atoms, such asi-propyl, i- or t-butyl, -pentyl or -hexyl, and a lower alkyleneiminogroup is preferably pyrrolidino, piperidino or hexamethyleneimino,either unsubstituted or preferably substituted in positions 2 or 3 byhydroxy, lower alkoxy or alkanoyloxy, e.g. those mentioned above, orhigher alkanoyloxy, e.g. octanoyloxy, decanoyloxy, undecanoyloxy,lauroyloxy, myristoyloxy, palmitoyloxy or stearoyloxy. Said 2 or 3position preferably carries in addition to hydrogen or said other groupsalso a lower alkyl group, preferably said secondary or teriary alkylgroups; a HPh-lower alkyl group, e.g. benzyl, 1- or 2-phenethyl; butpreferably a phenyl group HPh as illustrated above; furthermore, 1- or2-naphthyl optionally substituted as shown for HPh; unsubstituted 2- or3-furyl or -thiophenyl; 2-, 3- or 4-pyridyl; 2- or 3-(1-benzofuryl or1-benzothiophenyl); 2-, 3- or 4-quinolyl or 1-, 3- or 4-isoquinolyl, orsaid groups substituted by one to three lower alkyl, preferably methylgroups; or preferably said unsubstituted 2-oxo-1-benzimidazolyl group.

The symbol M represents preferably lithium, sodium or potassium, butalso one equivalent of magnesium or calcium, and the hydroxy ion in step4 is preferably provided from a strong base, such as an alkali metalhydroxide, e.g. potassium hydroxide, or a strong quaternary nitrogenbase, such as a lower trialkylbenzylammonium hydroxide.

In case step 2 is carried out with a compound II, wherein R is loweralkanoyloxy, the epoxidizing agent R₄ OOH may be hydrogen peroxide inthe presence of an organic nitrile, preferably a HPh-CN, such asbenzonitrile. In case R is CHO, both the Baeyer-Villiger reaction andepoxidation consume one mole equivalent of one of said peracids each,such as peracetic, pertrifluoroacetic, perbenzoic, 3-chloroperbenzoic,persuccinic or monoperphthalic acid. Depending on the use of the cis- ortrans-olefins, the stereospecific course of this process is guaranteed.

The above-mentioned reaction steps are carried out according to standardmethods, in the presence or absence of diluents, preferably such as areinert to the reagents and are solvents thereof, of catalysts, condensingor said other agents respectively and/or inert atmospheres, at lowtemperatures, room temperature or elevated temperatures, preferably atthe boiling point of the solvents used, at atmospheric orsuperatmospheric pressure. Thus, for example, the condensation steps 1and 4 are preferably carried out in an aqueous medium, which may containphase-transfer agents, such as tetra-lower alkylammonium hydroxides,e.g. tetrabutylammonium hydroxide, or crown-ethers, and/or loweralkanols, e.g. methanol, ethanol or isopropanol. If said water-misciblesolvents are replaced in step 4 by water-immiscible solvents, such asaliphatic ethers or halides, e.g. diethyl ether or methylene chloride,or hydrocarbons, e.g. cyclohexane or benzene, the condensation can bestopped at the preceding halohydrin stage.

The peroxidation should be carried out in low boiling haloalkanes, e.g.methylene chloride for said aromatic peracids; lower alkyl alkanoates,e.g. ethyl acetate, for aliphatic peracids; dimethylformamide forsuccinoyl peroxide; and benzonitrile with an alkali metal bicarbonate,e.g. potassium bicarbonate, for hydrogen peroxide. Said bicarbonates orcarbonates may also be used with pertrifluoroacetic acid, which destroyany excess of the peracid after the olefin has been consumed.

The optional condensation step 3 is advantageously carried out in anexcess of the amine HR₃ ' only, or in the presence of a di-loweralkylformamide, e.g. dimethylformamide.

The invention further includes any variant of the present process, inwhich an intermediate product obtainable at any stage of the process isused as a starting material and any remaining steps are carried out, orthe process is discontinued at any stage thereof, or in which thestarting materials are formed under the reaction conditions, or indifferent sequence, or they are used in the form of their salts oroptically pure antipodes. Thus for example, step 1 may also be carriedout with the free bisphenole and the epoxide of the olefin, to yieldcompounds III, with R' being also hydroxy, directly. Said phenols III orIV can also be obtained by reacting the formates III or IV first with ahydrolyzing agent other than said bases, such as a tri-lower alkylamide,e.g. triethylamine, whereupon the ring-closure to the dioxans V or I isachieved with said inorganic or ammonium bases. Mainly those startingmaterials would be used in said reactions, that lead to the formation ofthose compounds indicated above as being especially valuable, e.g. thosementioned in said patents.

Said compounds so obtained can be converted into each other according toknown methods. Thus, for example, compounds of Formula I with R₃ ═X canbe reacted with HR₃ ' analogous to step 3, advantageously in a loweralkanol, e.g. ethanol or isopropanol, or said other diluents; or with anaqueous base, e.g. an alkali metal hydroxide or carbonate, in order toobtain the glycols with R₃ ═OH. Moreover, in compounds of Formula II orIII any group CH₂ X can either be converted into another such group,e.g. chloromethyl into bromo- or iodomethyl, or into another esterifiedhydroxymethyl group, such as lower alkanoyloxymethyl, e.g.acetoxymethyl, the latter advantageously in compounds II. This can beachieved by reacting said compounds II or III with an alkali metal loweralkanoate or halide respectively, e.g. sodium acetate, bromide oriodide, in order to facilitate either epoxidation, or amination with HR₃'. Compounds of Formula V can be re-converted into the halohydrins Iwith R₃ ═X, by reaction with a hydrogen halide, e.g. hydrogen bromide,in an inert solvent, preferably a halogenated aliphatic, hydrocarbon,such as methylene chloride.

Finally, the compounds of Formula I are either obtained in the freeform, or as a salt thereof. Any resulting base can be converted into acorresponding acid addition salt, preferably with the use of atherapeutically useful acid or anion exchange preparation, or resultingsalts can be converted into the corresponding free bases, for example,with the use of a stronger base, such as a metal or ammonium hydroxide,basic salt or cation exchange preparation, e.g. an alkali metalhydroxide or carbonate. Said acid accition salts are preferably such oftherapeutically acceptable inorganic or organic acids, such as strongmetalloidic acids, for example hydrohalic, e.g. hydrochloric,hydrobromic or hydriodic acid; sulfuric, phosphoric, nitric orperchloric acid; aliphatic or aromatic carboxylic or sulfonic acids,e.g. formic, acetic, propionic, succinic, glycollic, lactic, malic,tartaric, citric, ascorbic, maleic, hydroxymaleic, pyruvic,phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic,salicylic, 4-aminosalicylic, pamoic, nicotinic; methanesulfonic,ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic,halogenbenzenesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilicor cyclohexylsulfamic acid. These or other salts, for example, thepicrates, can also be used for purification of the base obtained; thebases are converted into salts, the salts are separated and the basesare liberated from the salts. In view of the close relationship betweenthe free compounds and the compounds in the form of their salts,whenever a compound is referred to in this context, a corresponding saltis also intended, provided such is possible or appropriate under thecircumstances.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees/centigrade, and all parts wherever given are parts by weight.If not mentioned otherwise, all evaporations are performed under reducedpressure, preferably between about 15 and 100 mmHg.

The new compounds of the invention are those of Formula III and IV,wherein Ph is preferably 1,2-phenylene unsubstituted or monosubstitutedby hydroxy, benzyloxy, fluoro, chloro, bromo, trifluoromethyl, nitro,alkyl, alkoxy or alkanoyloxy with 1-4 carbons or alkylenedioxy with 1 or2 carbons, R' is hydroxy or alkanoyloxy with 1-4 carbons, one of Y and Zis R₂ and the other is chloro, bromo, iodo, C₁ -C₄ -alkanesulfonyloxy oralkanoyloxy)methyl, and each of R₁ and R₂ is hydrogen or methyl; or oneof Y' and Z' is R₂ and the other is CH₂ -R₃ ' in which R₃ ' ismono-alkylamino containing secondary or tertiary alkyl groups with 3 to7 carbon atoms, or lower alkyleneimino unsubstituted or substituted inpositions 2 or 3 by hydroxy, lower alkoxy, lower alkanoyloxy, higheralkanoyloxy, and/or said secondary or tertiary alkyl, HPh-lower alkyl,HPh, 1- or 2-naphthyl optionally substituted as shown for HPh;unsubstituted 2- or 3-furyl or -thiophenyl; 2-, 3- or 4-pyridyl; 2- or3-(1-benzofuryl or 1-benzothiophenyl); 2-, 3- or 4-quinolyl, 1-, 3- or4-isoquinolyl, or 2-oxo-1-benzimidazolyl or said heterocyclicssubstituted by 1 to 3 lower alkyls; or an acid addition salt thereof.

More preferred are said compounds III and IV, wherein Ph is1,2-phenylene unsubstituted or monosubstituted by methyl, methoxy,methylenedioxy, benzyloxy, formyloxy, acetoxy, fluoro, chloro,trifluoromethyl or nitro, R' is hydroxy, formyloxy or acetoxy, one of Yand Z is hydrogen and the other is chloromethyl, bromomethyl,iodomethyl, acetoxymethyl or mesyloxymethyl and R₁ is hydrogen; or oneof Y' and Z' is hydrogen and the other is CH--R₃ ' in which R₃ ' isi-porpylamino, i- or t-butylamino, -pentylamino or -hexylamino;pyrrolidino, piperidino or hexamethyleneimino unsubstituted orsubstituted in positions 2 or 3 by hydroxy, C₁ -C₄ alkoxy or C₁ -C₁₈-alkanoyloxy and HPh or 1-R₁ -2-oxo-1-benzimidazolyl, or an acidaddition salt thereof.

Most preferred are compounds of Formulae III and IV, wherein Ph is1,2-phenylene, 3-methoxy-1,2-phenylene or 5-chloro-1,2-phenylene, R' isformyloxy, one of Y and Z is hydrogen and the other is chloromethyl,iodomethyl acetoxymethyl or mesyloxymethyl and R₁ is hydrogen; or one ofY' and Z' is R₂ and the other is CH₂ --R₃ ' in which R₃ ' ist-butylamino, 4-hydroxy-4-phenylpiperidino or 2-oxo-1-benzimidazolyl, oran acid addition salt thereof.

EXAMPLE 1

To 1.2 lt of refluxing water, 1 ml of 40% aqueous tetrabutylammoniumhydroxide, 125 ml of salicylaldehyde and 150 ml ofcis-1,4-dichloro-2-butene are added while vigorously stirring, followedby the dropwise addition of the solution of 42 g of sodium hydroxide in200 ml of water at such a rate that the pH of the mixture is keptbetween 7 and 8. Thereafter the mixture is refluxed until the pH isabout 7, cooled and extracted with methylene chloride. The extract iswashed with 5% aqueous sodium hydroxide, dried, evaporated, the residuedistilled and the fraction boiling at 137°-140°/0.1 mmHg collected, toyield the 2-(4-chloro-cis-2-butenyloxy)-benzaldehyde.

To the solution of 24 g thereof in 500 ml of methylene chloride 0.2 g of2,4,6-tributylphenol and 55 g of 85% 3-chloroperbenzoic acid are addedand the mixture is refluxed for 3 days. It is cooled, filtered and thefiltrate washed with 5% aqueous sodium sulfite and 5% aqueous sodiumbicarbonate, dried and evaporated, to yield the2-(4-chloro-cis-2,3-epoxybutyloxy)-phenol formate, showing NMR-peaks at3.4, 3.6, 4.2, 6.9 and 8.25 ppm.

To the solution of 4.6 g thereof in 24 ml of methanol is added dropwise24 ml of 10% aqueous potassium hydroxide while stirring under nitrogenand maintaining the temperature below 30°. After stirring for 18 hoursat room temperature the mixture is partly evaporated, the residue takenup in water and the mixture extracted with diethyl ether. The extract iswashed with water, dried evaporated, the residue distilled and thefraction boiling at 120°/0.2 mmHg collected, to yield the d,l-threo- or(R-S)(S-R)-2-oxiranyl-1,4-benzodioxan of the formula ##STR9##

EXAMPLE 2

Replacing in Example 1 the cis-1,4-dichloro-2-butene by the same amountof trans-1,4-dichloro-2-butene and following the procedure as describedin said example, the 2-(4-chloro-trans-2-butenyloxy)-benzaldehyde isobtained, boiling at 147°-148°/0.15 mmHg (mentioned in German Pat. No.1,926,023 without details as to preparation).

24 g thereof are oxidized as described previously, to yield the2-(4-chloro-trans-2,3-epoxybutyloxy)-phenol formate, showing NMR-peaksat 3.2, 3.5, 4.1, 7.0 and 8.2 ppm.

4.6 g thereof are ring-closed as illustrated by Example 1, to yield thed,l-erythro- or (R--R)(S--S)-2-oxiranyl-1,4-benzodioxan of the formula##STR10## boiling at 120°/0.2 mmHg. The product crystallizes m.p. 45°.

EXAMPLE 3

To the solution of 6 g of sodium iodide in 150 ml of acetone 5 g of2-(4-chloro-cis-2,3-epoxybutyloxy)-phenol formiate are added and themixture stirred for 24 hours at room temperature in the dark. It isfiltered, the filtrate evaporated and the residue taken up in water. Themixture is extracted with methylene chloride, the extract dried andevaporated, to yield the 2-(4-iodo-cis-2,3-epoxybutyloxy)-phenolformate.

It is dissolved in 25 ml of dimethylformamide and 3.5 g of4-hydroxy-4-phenylpiperidine are added while stirring, followed by 5 mlof triethylamine. The mixture is stirred at 25° for 2 days in the dark,diluted with water, filtered and the residue washed with water, to yieldthe 2-[4-(4-hydroxy-4-phenylpiperidino)-cis-2,3-epoxybutyloxy]-phenolformate.

The solution of 3 g thereof in 12 ml of methanol is added dropwise to 12ml of 10% aqueous potassium hydroxide while stirring under nitrogen andmaintaining the temperature below 30°. After stirring for 18 hours atroom temperature the mixture is evaporated, the residue taken up inwater and the mixture extracted with diethyl ether. The extract iswashed with water, dried and evaporated. The residue is recrystallizedfrom isopropanol, to yield thed,l-threo-2-[2-(4-hydroxy-4-phenylpiperidino)-1-hydroxyethyl]-benzodioxanmelting at 116°-118°.

EXAMPLE 4

The mixture of 3 g of d,l-erythro-2-oxiranyl-1,4-benzodioxan, 1.9 g of4-hydroxy-4-phenylpiperidine and 20 ml of isopropanol is refluxed for 7hours. After cooling to room temperature 0.7 ml of methanesulfonic acidare added while stirring and the mixture is allowed to stand in therefrigerator overnight, to yield thed,l-erythro-2-[2-(4-hydroxy-4-phenylpiperidino)-1-hydroxyethyl]-1,4-benzodioxanmethanesulfonate, melting after recrystallization from aqueousisopropanol-diethyl ether at 212°-213°.

1 g thereof is suspended in 20 ml of water, the mixture made basic withaqueous sodium hydroxide and extracted with methylene chloride. Theextract is dried, evaporated and the residue recrystallized fromisopropanol, to yield the corresponding free base melting at 118°. It isidentical with that disclosed in U.S. Pat. No. 3,914,238.

EXAMPLE 5

The mixture of 3 g of d,l-threo-2-oxiranyl-1,4-benzodioxan and 20 ml oftert. butylamine is heated in a sealed tube to 100° for 10 hours andthen evaporated. The residue is taken up in aqueous ammonia, the mixtureextracted with chloroform, the extract dried, evaporated and the residuerecrystallized from petroleum ether, to yield the d,l-threo-2-(2-tert.butylamino-1-hydroxyethyl)-benzodioxan melting at 84°-85°.

It is dissolved in the minimum amount of ethanol, the solution acidifiedwith etanolic hydrogen chloride and diluted with diethyl ether, to yieldthe corresponding hydrochloride, melting at 192-194 afterrecrystallization from ethanol; it is identical with that described inU.S. Pat. No. 3,312,592.

Replacing said d,l-threo-2-oxiranyl-1,4-benzodioxan by the same amountof the erythro-enantiomer the d,l-erythro-2-(2-tert.butylamino-1-hydroxyethyl)-benzodioxan is obtained, melting at 93°-96°,and the hydrochloride thereof at 155°-157°.

EXAMPLE 6

To the stirred solution of 0.2 molar 3-chloro-perbenzoic acid in 275 mlof methylene chloride is added the solution of 25 gcis-1,4-dichloro-2-butene in 50 ml of methylene chloride. The mixture isstirred at room temperature for 4 days, filtered and the filtratestirred for 30 minutes with 100 ml of 10% aqueous sodium sulfite. Theorganic layer is separated, washed with cold 12% aqueous sodiumhydroxide and water, dried and evaporated to yield thecis-1,4-dichloro-2,3-epoxybutane boiling at 83°-85°/25 mmHg.

The mixture of 1.7 g thereof, 1.1 g of catechol and 2 ml of isopropanolis heated to 65° and the solution of 0.8 g of sodium hydroxide in 2 mlof water is added dropwise while stirring. The mixture is heated to 85°for 60 minutes, cooled and diluted with benzene. It is washed withwater, dried and evaporated, to yield a mixture comprising 48% startingepoxide; 40% desired d,l-threo-2-oxiranyl-benzodioxane and 10% of2-chloromethyl-3-hydroxymethyl-benzodioxane (by mass-spectroscopy). Itis separated by bulb to bulb-distillation and the fraction boiling at120°/0.2 mmHg collected, to yield said threo-compound.

EXAMPLE 7

To 1.2 lt of refluxing water, 1 ml of 40% aqueous tetrabutylammoniumhydroxide, 160 g of 5-chloro-salicylaldehyde and 140 ml oftrans-1,4-dichloro-2-butene are added while vigorously stirring,followed by the dropwise addition of the solution of 42 g of sodiumhydroxide in 200 ml of water at such a rate that the pH of the mixtureis kept between 7 and 8. Thereafter the mixture is refluxed until the pHis about 7, cooled and extracted with methylene chloride. The extract iswashed with 5% aqueous sodium hydroxide, dried, evaporated and theresidue heated to 30°/0.1 mmHg in order to remove the excess of1,4-dichloro-2-butene. The residue is taken up in 1 lt of diethyl ether,the solution filtered, the filtrate evaporated and the residuerecrystallized from ethyl acetate, to yield the5-chloro-2-(4-chloro-trans-2-butenyloxy)-benzaldehyde melting at62°-63°.

The mixture of 6 g thereof, 20 g of 3-chloroperbenzoic acid and 200 mlof methylene chloride is refluxed for 3 days. It is cooled, filtered andthe filtrate washed with 5% aqueous sodium sulfite and 5% aqueous sodiumbicarbonate, dried and evaporated, to yield the5-chloro-2-(4-chloro-trans-2,3-epxoybutyloxy)-phenol formate showingNMR-peaks at 3.3, 3.6, 4.2 and 8.2 ppm.

To the stirred solution of 7 g thereof in 25 ml of methanol 30 ml of1.75 N aqueous potassium hydroxide are added while cooling and themixture is stirred for 18 hours at room temperature. It is diluted withwater, extracted with diethyl ether, the extract washed with water,dried and evaporated to yield thed,l-erythro-6-chloro-2-oxiranyl-1,4-benzodioxan as an oil, showingNMR-peaks at 2.8, 3.0 and 6.4 ppm and boiling (bulb to bulb) at 130°/0.2mmHg.

EXAMPLE 8

Replacing the 4-chloro-salicylaldehyde by 152 g of o-vanillin andfollowing the exact procedure given in Example 7, the2-(4-chloro-trans-2-butenyloxy)-3-methoxybenzaldehyde is obtained,boiling at 165°/0.15 mmHg.

The mixture of 7 g thereof, 21 g of 3-chloroperbenzoic acid and 250 mlof methylene chloride is refluxed for 3 days. It is cooled, filtered andthe filtrate washed with 5% aqueous sodium sulfite and 5% aqueous sodiumbicarbonate, dried and evaporated, to yield the2-(4-chloro-trans-2,3-epoxybutyloxy)-3-methoxyphenol formate, showingNMR-peaks at 3.2, 3.6, 3.9, 4.15 and 8.3 ppm.

To the stirred solution of 8 g thereof in 20 ml of methanol 35 ml of1.75 N aqueous potassium hydroxide are added while cooling and themixture is stirred for 18 hours at room temperature. It is concentratedto about half its volume, diluted with 50 ml of water and extracted withdiethyl ether. The extract is washed with water, dried and evaporated toyield the d,l-erythro-8-methoxy-2-oxiranyl-1,4-benzodioxan as an oil,showing NMR-peaks at 2.8, 3.1, 3.8 and 6.5 ppm.

EXAMPLE 9

The mixture of 50 g of 2-(4-chloro-trans-2-butenyloxy)-benzaldehyde, 50g of sodium acetate and 200 ml of acetic acid is refluxed for 2 hoursand concentrated. The concentrate is diluted with water, extracted withdiethyl ether, the extract washed with water and 5% aqueous sodiumbicarbonate, dried and evaporated, to yield the2-(4-acetoxy-trans-2-butenyloxy)-benzaldehyde.

The mixture of 25 g thereof, 51 g of 3-chloroperbenzoic acid and 500 mlof methylene chloride is refluxed for 3 days. It is cooled, filtered andthe filtrate washed with 5% aqueous sodium bicarbonate, dried andevaporated, to yield the 2-(4-acetoxy-trans-2,3-epoxybutyloxy)-phenolformate.

To the stirred solution of 10 g thereof in 50 ml of methanol is 110 mlof 1.75 N aqueous potassium hydroxide are added while cooling and themixture is stirred for 18 hours at room temperature and 2 hours at 50°.It is concentrated, the concentrate diluted with water, extracted withmethylene chloride, the extract washed with water, dried and evaporatedto yield the d,l-erythro-1,4-benzodioxan-2-yl-ethyleneglycol.

To the stirred solution of 5.6 g thereof in 20 ml of pyridine 2.3 ml ofmethanesulfonyl chloride are added while cooling to keep the temperatureat about 20°. Stirring is continued for 10 minutes and the mixture,containing the mono-mesylate, is diluted with 200 ml of diethyl ether.It is stirred at 25° and 10 g of sodium methoxide are slowly added whilemaintaining said temperature. After stirring for 1 hour the mixture istreated with 200 g of ice, the organic layer separated, washed with 5%hydrochloric acid until neutral, dried and evaporated. The residue isdiltilled and the fraction boiling at 120°/0.2 mmHg collected, to yieldthe d,l-erythro-2-oxiranyl-1,4-benzodioxane, melting at 45°, insubstantially higher yield.

EXAMPLE 10

The mixture of 2.5 g of d,l-erythro-2-oxiranyl-1,4-benzodioxan, 1.7 g of2-(2-oxo-1-benzimidazolyl)-piperidine and 15 ml of isopropanol isrefluxed for 4 hours and concentrated to a small volume. The concentrateis diluted with benzene and extracted with 5% hydrochloric acid. Theextract is allowed to stand in the cold, the gummy precipitate formed,filtered off and triturated with aqueous ammonia and chloroform. Theorganic solution is separated, dried, evaporated and the residuerecrystalized from ethyl acetate, whereby thed,l-erythro-2-[2-(4-(2-oxo-1-benzimidazolyl)-piperidino)-1-hydroxyethyl]-1,4-benzodioxanis obtained, melting at 188°-190°; it is identical to that of GermanPat. No. 2,400,094.

The analogously obtained d,l-threo-compound melts at 110°-115°.

EXAMPLE 11

5 g of d,l-erythro-2-oxiranyl-1,4-benzodioxan are treated with thesolution of 2.4 g of hydrogen bromide in 100 ml of methylene chloridewhile stirring. The solution formed is allowed to stand overnight atroom temperature and evaporated, to yield thed,l-erythro-2-(2-bromo-1-hydroxyethyl)-1,4-benzodioxan showing NMR-peaksbetween 3.7 and 4.5, as well as at 6.9 ppm.

EXAMPLE 12

The solution of 10.9 g of5-chloro-2-(4-chloro-trans-2,3-epoxybutyloxy)-phenol formate in 200 mlof anhydrous diethyl ether is stirred with 43 ml of 1.75 N aqueouspotassium hydroxide and 0.2 ml of 40% aqueous tetrabutylammoniumhydroxide for 18 hours at room temperature. The organic layer isseparated, washed with water, dried and evaporated, to yield thed,l-erythro-6-chloro-2-(2-chloro-1-hydroxyethyl)-1,4-benzodioxan as anoil showing NMR peaks at 3.0, between 3.8 and 4.25 and at 6.7 ppm.

EXAMPLE 13

To 2 lt of refluxing water, 3 ml of 40% aqueous tetrabutylammoniumhydroxide, 250 ml of salicylaldehyde and 280 ml oftrans-1,4-dichloro-2-butene are added while vigorously stirring,followed by the dropwise addition of the solution of 83 g of sodiumhydroxide in 400 ml of water at such a rate that the pH of the mixtureis kept between 7 and 8 (ca 25 minutes). Thereafter the mixture isrefluxed for about 6 minutes until the pH is about 7, cooled to 20° andthe aqueous layer is extracted with diethyl ether. The extract iscombined with the organic layer, washed with 5% aqueous sodiumhydroxide, dried, evaporated, the residue distilled and the fractionboiling at 141°-147°/0.7 mmHg collected, to yield the2-(4-chloro-trans-2-butenyloxy)-benzaldehyde.

To the solution of 155.7 g thereof in 3.8 lt of methylene chloride 357 gof 85% 3-chloro-perbenzoic acid are added and the mixture is stirred forone hour and refluxed for 4 days. It is cooled, filtered and thefiltrate washed with methylene chloride and saturated aqueous sodiumbicarbonate, dried and evaporated below 40°, to yield the2-(4-chloro-trans-2,3-epoxybutyloxy)-phenol formate, showing NMR-peaksat 3.2, 3.5, 4.1, 7.0 and 8.2 ppm.

To the solution of 229.4 g thereof in 900 ml of methanol is addeddropwise 1.1 lt of 10% aqueous potassium hydroxide while stirring undernitrogen and maintaining the temperature between 8° and 15°. Afterstirring at said temperature overnight and at room temperature themixture is decanted from the residue and extracted with diethyl ether.The combined residue and extract is washed with water, dried, evaporatedand the residue recrystallized from diethyl ether, to yield thed,l-erythro-2-oxiranyl-1,4-benzodioxan melting at 50°-53°; it isidentical with that obtained according to Example 2.

We claim:
 1. A compound of the formula ##STR11## wherein Ph isunsubstituted 1,2-phenylene or 1,2-phenylene substituted by one memberselected from lower alkoxy and halogeno, R' is formyloxy, one of Y and Zis R₂ and the other is chloromethyl, bromomethyl or iodomethyl, and eachof R₁ and R₂ is hydrogen or lower alkyl.
 2. A compound as claimed inclaim 1, wherein Ph is 1,2-phenylene unsubstituted or monosubstituted byfluoro, chloro, bromo, or alkoxy with 1-4 carbons, R' is formyloxy, oneof Y and Z is R₂ and the other is (chloro, bromo or iodo)-methyl, andeach of R₁ and R₂ is hydrogen or methyl.
 3. A compound as claimed inclaim 1, wherein Ph is 1,2-phenylene unsubstituted or monosubstituted bymethoxy, fluoro or chloro, R' is formyloxy, one of Y and Z is hydrogenand the other is chloromethyl, bromomethyl or iodomethyl, and each of R₁and R₂ is hydrogen.
 4. A compound as claimed in claim 1, wherein Ph is1,2-phenylene, 3-methoxy-1,2-phenylene or 5-chloro-1,2-phenylene, R' isformyloxy, one of Y and Z is hydrogen and the other is chloromethyl oriodomethyl and R₁ is hydrogen.